Although it had been known since the 1920's that many atomic nuclei have angular momentum arising from their inherent property of rotation, or spin and that each nucleus of nonzero spin has a magnetic moment or dipole associated with it, it wasn't until 1948 that the first nuclear magnetic resonance method was developed as a tool applied to studies of structural chemistry and it was not until the late 1970's that the method found application in clinical diagnosis.
Nuclear magnetic resonance imaging is based on the manipulation of an entire population of nuclei by the exposure of the nuclei to an external magnetic field, altering the characteristics of said field and measuring the response of the nuclei thereto.
The magnetic behavior of the entire population of nuclei can be defined by the macroscopic or bulk magnetization vector, which represents the net effect of all of the magnetic moments of all of the nuclei of a given species in the sample being analyzed. In the absence of an external magnetic field, the magnetic dipoles will be pointing in random directions hence the bulk magnetization will be zero. However, when the population of nuclei is exposed to an external magnetic field the dipoles become oriented, pointing in a direction parallel to the applied field.
Once the external magnetic field has been applied and the bulk magnetic moment of the population has been established, the next phase of the analysis involves perturbing the oriented nuclei. The perturbation is accomplished by the application of a second magnetic field at right angles to the first and alternating in polarity. The analogy of a spinning top or gyroscope has been applied to illustrate the effect of this second magnetic field. The spinning nuclei are represented as spinning tops or gyroscopes and because of the influence of the initial magnetic field all of the axes of the gyroscopes are pointed vertically. If the axis of a spinning gyroscope is tipped away from the vertical, the gyroscope will continue to rotate about the former vertical axis in a motion describing the wall of an inverted cone. This motion is known as precession. Similarly, the bulk magnetization vector can be caused to precess about its original axis under the "tipping" influence of a second magnetic field. It should be understood that in order to tip the macroscopic spin vector away from its original axis, the applied electromagnetic radiation must match (i.e. be in resonance with) the natural precessional frequency of the nuclei of the sample, hence the term nuclear magnetic resonance (NMR).
A simple mathematical relation links the resonance frequency, often called the Larmor frequency, to the value of the externally applied static magnetic field. The frequency is equal to the strength of the field multiplied by the "gyromagnetic ratio," which is unique for each nuclear species of nonzero spin. For hydrogen nuclei (protons) in a magnetic field of one tesla (10,000 gauss) the resonance frequency is 42.57 megahertz (MHz), or 42.57 million cycles per second. For nuclei of the isotope phosphorus 31(.sup.31 P) in the same field the resonance frequency is 17.24 MHz; for nuclei of sodium 23(.sup.23 Na) it is 11.26 MHz. These frequencies are far below those of X-rays or even visible light and as such are powerless to disrupt the molecules of living systems, hence providing one of the major desirable features of this type of analysis when applied to diagnostic scanning.
During the perturbation caused by the application of the second field many of the nuclei which are in a low energy state (i.e. their magnetic moments are aligned with the first (static) magnetic field) undergo a transition to a higher energy state (i.e. their magnetic moments tend to be aligned with the second (rotating or alternating) field. The displacement angle between the nuclear magnetization vector and the direction of the static magnetic field continues to increase as long as the competing rotating field is applied and the rate of increase depends on the power of the field. A pulse long and strong enough to tip the bulk vector from its original position to one which is parallel to the rotating field is known as a 90.degree. pulse owing to the perpendicular arrangement of the two magnetic fields. Precession pattern of nuclei under these conditions resemble a flattened disc rather than a cone.
Once the external energy source of alternating frequency is removed, the nuclei in the excited (high energy) state tend to revert to the more stable (low energy) state. This is accomplished by a remission of the energy at the same frequency (Larmor frequency) at which it was absorbed. It is the detection and analysis of this decay signal which forms the basis of the NMR imaging technology.
The return to equilibrium of the nuclei is characterized by two principal "relaxation times", T.sub.1 and T.sub.2. The relaxation times T.sub.1 (spin-lattice or longitudinal relaxation time) and T.sub.2 (spin-spin or transverse relaxation time) are parameters which describe the exponential return to equilibrium of the nuclear magnetism of the sample nuclei in directions parallel or perpendicular, respectively, to the applied (i.e. rotating) magnetic field. The rate at which nuclei assume the ground state depends on how readily they can dispose of their excess energy. T.sub.1 represents a time constant describing one route for the dissipation of said energy, specifically the loss of energy to the local molecular environment (i.e. the lattice). T.sub.2, on the other hand, is a rate constant which describes a second route of dissipation, namely the loss of energy to other protons. This latter disposition of energy has the effect of dephasing many of the excited nuclei without loss of energy to the surrounding environment.
A variety of methods exist for converting the NMR resulting from free induction decay into an image. Damadian (Philos. Trans. R. soc. Lond. Biol. 289:111-121 (1980)) has taken the approach of displaying the intensity of the NMR signal from discrete points in the human anatomy on a coordinate grid. This method depends on the shape of the magnetic field produced by the particular magnet configuration employed to focus on a given point within the body. The magnetic field used has been described as "saddle shaped", and its strength is said to vary appreciably within very small distances along the sloping surface of this configuration. The field center (or "saddle point") is used as the reference to choose an exciting RF frequency to achieve the resonance condition. Using this technique, an image is created by moving the body area to be examined through the saddle point in an ordered fashion so that a recognizable structure will be achieved from the signal determinations at each location of interest.
Lauterbur and Lai (I.E.E.E. Trans. Nucl. Sci. 27:1227-31 (1980)) have described a method of image reconstruction involving the analysis of many planes of NMR signals in a manner similar to X-ray computed tomographic (CT) images. In this technique, known as zeugmatography, signals from the sample volume are contained in each one-dimensional projection. Imaging may be achieved by superimposing a linear magnetic field gradient on the area of interest (e.g., human anatomic area or organ) that has been placed in a uniform magnetic field. The resonance frequencies of the precessing nuclei will depend on their position along the direction of the magnetic gradient. If one obtains a series of one-dimensional projections at different gradient orientations, two- and three-dimensional images of the structure or organ of interest can be obtained by this technique.
Other techniques may isolate a point, line, or plane within the human body by use of oscillating magnetic field gradients, as for example described by Hinshaw et al. (Br. J. Radiol. 51:273-280 (1978)).
Although a potentially useful system, NMR imaging is plagued with several problems. Firstly, NMR is much less sensitive than other forms of spectroscopy and secondly, its use is restricted to certain atomic nuclei. Three nuclei have been used almost exclusively in biological NMR imaging studies, the hydrogen atom or proton (.sup.1 H), .sup.31 phosphorus (.sup.31 P), and .sup.13 carbon (.sup.13 C). Of the three the proton gives the strongest signal but is so ubiquitous in living tissue that special techniques are necessary to resolve individual signals from a multitude of overlapping peaks. The most abundant isotope of carbon is .sup.12 C, which possesses no nuclear spin. Only 1% of natural carbon is .sup.13 C which yields a much weaker signal than the proton. Most NMR work on intact biological systems has centered on .sup.31 P, the naturally occurring isotope of phosphorus, but this nucleus only gives a signal one-sixth the strength of the proton.
Several attempts have been made to try to overcome the low sensitivity of NMR. For example a system whereby many spectra are summed (overlayed) has been employed. For biological work, the procedure is best carried out with pulsed NMR, in which short, powerful bursts of radiation at many frequencies are given to the sample. Each resultant signal contains all the information required to generate an entire spectrum by the mathematical process of Fourier transformation but in practice it is usual to add together many signals before transforming them in order to obtain a sufficient signal/noise ratio.
One further aspect of NMR spectroscopy must be mentioned: the time taken for the nuclei perturbed by the radiofrequency signal to relax back to their unperturbed state. This obviously limits the rate at which pulses can usefully be administered to the sample.
Investigations by Brady, T. J. et al. (Radiology 143:343-347 (1982)) and Ujeno, Y. (Physiol. Chem. & Physics 12:271-275 (1980)) have sought to enhance proton signals by the addition of substances which affect the T.sub.1 and T.sub.2 relaxation times of the NMR-sensitive nuclei. As will be apparent from the discussion to follow, one object of the instant invention is to enhance NMR-imaging, not by affecting T.sub.1 /T.sub.2 per se, but rather to focus and concentrate the magnetic field which is applied to the sample, so that the sharpness of the signal is augmented (i.e., less dispersion in the peaks) whereby the resolution or clarity of the mapped signals, i.e., the image is enhanced.